Multiple sclerosis (MS) is a severely debilitating neurodegenerative disease marked by progressive demyelination and functional loss in the central nervous system (CNS) (Gold et al., 2006; Compston and Coles, 2008). Oxidative stress resulting from inflammation is known to play a critical role in demyelination, a major pathology in MS (Smith et al., 1999; Gilgun-Sherki et al., 2004). However, conventional free radical scavengers have been unsuccessful at preventing disease development or progression (Smith et al., 1999; Gold et al., 2006; Compston and Coles, 2008). Hence, a priority in MS research is to improve understanding of the mechanisms of oxidative stress and thereby identify novel, more effective therapeutic targets.
It has been discovered that in vivo production of acrolein may mediate the initiation and/or progression of multiple sclerosis. It has also been discovered herein that compounds capable of interacting with acrolein are efficacious in treating multiple sclerosis. Without being bound by theory, it is believed herein that compounds that are capable of scavenging and/or preventing acrolein from contacting tissues are efficacious in treating multiple sclerosis.
Acrolein, a reactive α,β-unsaturated aldehyde, has been reported to be a product of oxidative stress and lipid peroxidation. Furthermore, acrolein has been reported to remain active in the body for several days (Ghilarducci and Tjeerdema, 1995) while more commonly studied oxidative species decay within seconds (Halliwell and Gutteridge, 1999). Therefore, and without being bound by theory, it is believed herein that acrolein may be a key factor in perpetuating oxidative stress and may cause progressive myelin damage and functional loss. Accordingly, acrolein may be a potential novel target for MS therapeutics.
Described herein is the role of acrolein in the pathogenesis of MS using a well-established animal model of MS. Experimental autoimmune encephalomyelitis (EAE) was induced in mice, and acrolein levels were determined in control and experimental groups. It has also been discovered that hydrazinopyridazines, fused hydrazinopyridazines, phenylethylhydrazines, and combinations thereof are useful in treating multiple sclerosis.
In one illustrative embodiment of the invention, compounds of the following formula are described herein:
and pharmaceutically acceptable salts thereof, wherein:
R is independently selected in each instance from hydrogen, acyl, or sulfonyl; or alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; and
RA represents three substituents selected from the group consisting of hydrogen, halo, hydroxy and derivatives thereof, amino and derivatives thereof, thio and derivatives thereof, acyl, carboxylate or a derivative thereof, hydroxylamino and derivatives thereof, hydrazino and derivatives thereof, sulfinyl or a derivative thereof, or sulfonyl or a derivative thereof; or alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; or two of RA are taken together with the attached carbons to form an optionally substituted saturated, unsaturated, or aromatic carbocycle or heterocycle.
In one illustrative embodiment of the invention, compounds of the following formula are described herein:
and pharmaceutically acceptable salts thereof, wherein:
R is independently selected in each instance from hydrogen, acyl, or sulfonyl; or alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; and
RA represents three substituents selected from the group consisting of hydrogen, halo, hydroxy and derivatives thereof, amino and derivatives thereof, thio and derivatives thereof, acyl, carboxylate or a derivative thereof, hydroxylamino and derivatives thereof, hydrazino and derivatives thereof, sulfinyl or a derivative thereof, or sulfonyl or a derivative thereof; or alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; or two of RA are taken together with the attached carbons to form an optionally substituted saturated, unsaturated, or aromatic carbocycle or heterocycle.
In another embodiment, pharmaceutical compositions containing one or more of the compounds are also described herein. In one aspect, the compositions include a therapeutically effective amount of the one or more compounds for treating a patient with MS. It is to be understood that the compositions may include other components and/or ingredients, including, but not limited to, other therapeutically active compounds, and/or one or more carriers, diluents, excipients, and the like.
It is appreciated herein that the compounds described herein may be used alone or in combination with other compounds useful for treating MS, including those compounds that may be therapeutically effective by the same or different modes of action. In addition, it is appreciated herein that the compounds described herein may be used in combination with other compounds that are administered to treat other symptoms of MS.
In another embodiment, methods for using the compounds and pharmaceutical compositions for treating patients with MS are also described herein. In one aspect, the methods include the step of administering one or more of the compounds and/or compositions described herein to a patient with MS. In another aspect, the methods include administering a therapeutically effective amount of the one or more compounds and/or compositions described herein for treating patients with MS. In another embodiment, uses of the compounds and compositions in the manufacture of a medicament for treating patients with MS are also described herein. In one aspect, the medicaments include a therapeutically effective amount of the one or more compounds and/or compositions for treating a patient with MS. In another embodiment, unit doses and/or unit dosage forms that include the compounds and pharmaceutical compositions for treating patients with MS are also described herein. In another aspect, the unit doses and/or unit dosage forms are administered to a patient with MS.
In another embodiment, compounds, compositions, methods, and uses are described herein for treating progressive forms of MS. In another embodiment, compounds compositions, methods, and uses are described herein for treating relapsing forms of MS.
In another embodiment, compounds, compositions, methods, and uses are described herein for treating early, mid, and/or late stage MS. In another embodiment, compounds, compositions, methods, and uses are described herein for prophylactically treating MS. It has been discovered herein that the compounds, compositions, methods, and uses described herein are effective in treating MS both before and after symptoms are observed. Illustratively, prophylactic treatment may be performed in patients who are at an increased risk of developing MS, such as patients having a history of relapsing MS, patients having a family history or relative with MS, and the like. Illustratively, prophylactic treatment may be performed in patients who do not have outwardly observable symptoms of the MS, but who show early damage to myelin, slow or inadequate myelin repair, high levels of acrolein, and the like. It has also been discovered herein that beginning treatment using the compounds, compositions, methods, and uses described herein earlier in the disease progression of MS may lead to better patient outcomes, such as but not limited to delayed onset of outwardly observable symptoms or more severe symptoms, overall improved amelioration of symptoms, and the like.